Recovery of Tendon Characteristics by Inhibition of Aberrant Differentiation of Tendon-Derived Stem Cells from Degenerative Tendinopathy

Abstract

The inhibition of the aberrant differentiation of tendon-derived stem cells (TDSCs) is a major target for the regeneration of damaged tendon tissues, as tendinopathy can be caused by the aberrant differentiation of TDSCs. We investigated whether the possible aberrant differentiation of TDSCs can be prevented by using adequate inhibitors. TDSCs extracted from chemically induced tendinopathy and injury-with-overuse tendinopathy models were cultured with 18α-glycyrrhetinic acid (AGA) and T0070907 to block osteogenic differentiation and adipogenic differentiation, respectively. The optimal dose of AGA decreased the osteogenic-specific marker Runx2 (Runt-related transcription factor 2), and T0070907 blocked the adipogenic-specific marker peroxisome proliferator-activated receptor gamma (PPARγ) in mRNA levels. We also found that AGA induced tenogenic differentiation in mRNA levels. However, T0070907 did not affect the tenogenic differentiation and regenerative capacity of TDSCs. We expect that optimal doses of AGA and T0070907 can prevent tendinopathy by inhibiting osteogenic and adipogenic differentiation, respectively. In addition, AGA and T0070907 may play important roles in the treatment of tendinopathy.

SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy

“… 24 , 26 SM04755 promoted dose‐dependent differentiation of hMSCs and rTDSCs into tenocytes expressing tenocyte markers Scleraxis A (SCXA), Tenomodulin (TNMD), Tenascin C (TNC), Mohawk (MKX), Thrombospondin 4 (THBS4), and Type I and Type III collagens produced by the tendon (Figures 1C,D and S3A,B), thus increasing the number of differentiated stained cells by ~4‐ to 10‐fold ( p < .0001) compared with DMSO‐treated control. Compared with DMSO control, expression of osteoblast genes (alkaline phosphatase [ ALPL ], osteocalcin [ BGLAP ], and RUNX2 ), 27 , 28 chondrocyte genes (aggrecan [ ACAN ], RUNX1, GDF5 , and SOX9 ), 20 and adipocyte genes (peroxisome proliferator‐activated receptor gamma [ PPARγ ], CCAAT/enhancer‐binding protein alpha [ C/EBPα ], and leptin [ LEP ]) 29 , 30 , 31 was significantly decreased ( p < .05) in SM04755‐treated hMSCs (Figure S3C–E). Moreover, expression of adiponectin ( ADIPOQ ), a hormone shown to increase tendon progenitor cell proliferation and differentiation, 32 was significantly increased ( p < .05) in cells treated with SM04755 compared with DMSO control (Figure S3E).…”

Caveolin-1 is involved in fatty infiltration and bone-tendon healing of rotator cuff tear

“…However, the inhibiting property of the cAMP/PKA pathway on the adipogenic differentiation of TSCs lacks available evidence to support and requires further studies. The tendinopathy can be caused by the aberrant differentiation of TSCs and the inhibition of the aberrant differentiation of TSCs is thus a major target for the regeneration of damaged tendon tissues (Kim et al 2020). Notably, the enhanced cAMP concentration aids in the treatment of Achilles tendon injury in rats (Rho et al 2020).…”